Glimepiride is prepared according to the original patent EP 031 058 (U.S. Pat. No. 4,379,785) either via reaction of 3-ethyl-4-methyl-2-oxo-2,5-dihydro-pyrrol-1-carbox-[2-(4-sulfamoyl-phenyl)ethyl]-amide of formula II
with trans-4-methylcyclohexylisocyanate of formula III
or via reaction of alkyl [4-(2-{[(3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]amino}ethyl)phenyl]sulfonyl carbamate of formula IV
wherein R is a C1-C5 alkyl, with trans-4-methylcyclohexylamine of formula V
trans-4-Methylcyclohexylisocyanate of formula III is again prepared from trans-4-methylcyclohexylamine of formula V.
For the production of glimepiride, the key factor is sufficient purity of trans-4-methylcyclohexylamine of formula V with the lowest possible content of the cis-isomer. The most commonly used procedure is reduction of 4-methylcyclohexanoneoxime of formula VI
with sodium in alcohols, most frequently in ethanol (T. P. Johnston, G. S. McCaleb, P. S. Opliger, W. R. Laster, J. A. Montgomery, J. Med. Chem. 1971, 14, 600-614). The amine obtained via this procedure typically contains between 8 to 10% of the cis-isomer (H. Booth, G. C. Gidley, P. R. Thornburrow, J. Chem. Soc. (B) 1971, 1047-1050). Further purification of the amine to a higher content of the trans-isomer via crystallization of its salts is not sufficiently documented. Earlier literature describes purification of crude trans-4-methylcyclohexylamine by crystallization of its hydrochloride, but in most cases neither yields nor the contents of the cis-isomer are given. The only rather detailed description of such purification is given in the above-mentioned paper (T. P. Johnston, G. S. McCaleb, P. S. Opliger, W. R. Laster, J. A. Montgomery, J. Med. Chem. 1971, 14, 600-614), wherein its authors have obtained, by triple crystallization in acetonitrile of the crude hydrochloride having the m.p. 250° C., a substance melting at 260° C., but in 27% yield.